Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa

// Lin Li 1, * , Yanwei Sha 2, * , Xi Wang 3 , Ping Li 2 , Jing Wang 4 , Kehkooi Kee 1 , Binbin Wang 3 1 Center for Stem Cell Biology and Regenerative Medicine, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China 2 Reproductive Medicine Center, Xiamen Maternal and Child Health Care Hospital, Xiamen, 361005, Fujian Province, China 3 Center for Genetics, National Research Institute for Family Planning, Haidian, Beijing, 100081, China 4 Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China * These authors have contributed equally to this work Correspondence to: Binbin Wang, email: wbbahu@163.com Kehkooi Kee, email: kkee@mail.tsinghua.edu.cn Keywords: acephalic spermatozoa, whole-exome sequencing, BRDT, mutation, RNA-sequencing Received: July 22, 2016 Accepted: October 19, 2016 Published: February 10, 2017 ABSTRACT Acephalic spermatozoa is a very rare disorder of male infertility. Here, in a patient from from a consanguineous family, we have identified, by whole-exome sequencing, a homozygous mutation (c.G2783A, p.G928D) in the BRDT gene. The gene product, BRDT, is a testis-specific protein that is considered an important drug target for male contraception. The G928D mutation is in the P-TEFb binding domain, which mediates the interaction with transcription elongation factor and might affect the transcriptional activities of downstream genes. By RNA-sequencing analysis of cells expressing the BRDT mutation, we found the p.G928D mutation protein causes mis-regulation of 899 genes compared with BRDT wild-type cells. Furthermore, by Gene Ontology analysis, the upregulated genes in p.G928D cells were enriched in the processes of intracellular transport, RNA splicing, cell cycle and DNA metabolic process, revealing the underlying mechanism of the pathology that leads to acephalic spermatozoa.